Colorectal cancer (CRC) is a leading cause of cancer-related morbidity and mortality in the United States. Surgical resection has proven to be an effective means of cure for early-stage CRC; however, survival rates plummet for patients with advanced disease. Initial or acquired resistance to chemotherapy is often the major limitation in disease management. One theory that has emerged to explain tumor resistance and recurrence is the existence of cancer stem cells (CSCs) that have the functional attributes of self-renewal and ability to reconstitute the entire cellular diversity of the original tumor. Importantly, CSCs of multiple tumor types have been identified by a similar signature of surface molecules found on matching normal stem cells. Both normal and cancer stem cells resist radiation and chemotherapy over non-stem cells despite a shared genetic background. This may be attributable to the fact that adult tissue stem cells have evolved adaptive mechanisms to maintain homeostatic and genomic integrity. In accord with the hypothesis that stem-like cells in cancer resist chemotherapy, the expression of CSC markers as well as the fraction of tumor-initiating cells is increased in tumors after treatment. In particular, expression of the intestina stem cell marker LGR5 (Leucine- rich repeat containing G-protein coupled Receptor 5) is upregulated in patient tumors with increasing clinical stage and can predict the likelihood of tumor recurrence. Here, I investigate LGR5 as a potential indicator of chemoresistant CSCs in human and murine models of CRC. In addition, I propose to interrogate the signaling pathways that emanate from this surface receptor and determine if the interruption of these survival mechanisms can sensitize tumors to chemotherapy. PUBLIC HEALTH RELEVANCE: Colorectal cancer is a major cause of death in the United States and abroad, mostly due to the failure of chemotherapy to eliminate tumor cells. This study focuses on the biology of a subpopulation of stem-like tumor cells identified by the surface receptor LGR5, which exhibit differential sensitivity and tumorigenicity as compared to tumor cells that lack LGR5 expression. Disruption of the chemotherapeutic resistance mechanisms in LGR5+ cells may sensitize tumors to established treatments.